Citalopram is a well-known antidepressant drug that has now been on the market for some years.
It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities.
Citalopram was first disclosed in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent publication i.a. outlines a process for preparation of citalopram from the corresponding 5-bromo-derivative by reaction with cuprous cyanide in a suitable solvent and by alkylation of 5-bromo-phtalane.
U.S. Pat. No. 4,943,590 corresponding to EP-B1-347 066 describes two processes for the preparation of escitalopram (S-enantiomer of citalopram). Both processes use the racemic diol having the formula
as starting material. According to the first process, the diol of formula (I) is reacted with an enantiomerically pure acid derivative, such as (+) or (−)-α-methoxy-α-trifluoromethyl-phenylacetyl chloride to form a mixture of diastereomeric esters, which are separated by HPLC or fractional crystallization, whereupon the ester with the correct stereochemistry is enantioselectively converted into escitalopram. According to the second process, the diol of formula (II) is separated into the enantiomers by stereoselective crystallization with an enantiomerically pure acid such as (+)-di-p-toluoyltartaric acid, whereupon the S-enantiomer of the diol of the formula (I) is enantioselectively converted to escitalopram.
Escitalopram has now been developed as an antidepressant. Hence, there is a desire for an improved method for preparation of escitalopram.
It has been found that the S-enantiomer of the diol of formula (I) above as well as acylated derivatives thereof may be prepared by selective enzymatic acylation of the primary hydroxyl group in the racemic diol to obtain S-diol of formula (I) or an acylated derivative thereof with high optical purity and further that the enantiomers obtained may be effectively separated by reaction of the diol of formula (I) with a compound which form a derivative of the diol of formula (I) containing a carboxylic acid group. The derivative formed precipitates once it is formed and may easily be separated from the reaction mixture.